This proposal is response to RFA-DE-05-001. Kaposi's sarcoma associated herpesvirus (KSHV) is etiologically linked to Kaposi's sarcoma (KS), the most common malignancy and oral cancer in AIDS patients. Unlike other DNA tumor viruses, KSHV lytic life cycle contributes significantly to the formation of KS lesions by facilitating viral spread to the target sites and releasing paracrine factors to support the growth of KS tumor cells. Recent study found that KSHV episomes in latently infected cells were rapidly lost due to cell proliferation, reactivation and infection processes constantly happen in KS lesion in order to maintain viral infected cell population. Reactivation and infection normally inevitably triggers host innate antiviral response including interferon (IFN) signaling pathway. However, KSHV evolved elaborate mechanism to evade IFN signaling which enable its recurring reactivation and infection process undetected by host immune surveillance system. We have found KSHV immediate early protein ORF45 interacts with cellular interferon regulatory factor-7 (IRF-7) and prohibits IRF-7 from being transported to the nucleus. As a result, ORF45 efficiently inhibits the induction of type I interferon during viral infection. In addition, ORF45 protein is also found in KSHV virion as tegument protein. The immediate-early expression kinetics as well as the presence of ORF45 in virion suggests critical roles of ORF45 in antagonizing host antiviral defenses and viral propagation. We hypothesize that KSHV uses ORF45 protein to ensure a protection from host immune responses and a successful viral infection and reactivation. In this proposal, first, we will investigate the mechanism that ORF45 use to block the IRF-7 activation and interferon induction. Second, we will examine the role of ORF45 in antagonizing host antiviral response with both gain-of-function and loss-of-function approach. Third, we will assess the impact of ORF45 on KSHV reactivation and pathogenicity by disrupting ORF45 gene function With SiRNA or recombinant ORF45 deficient KSHV. The proposed study will reveal the mechanism that viruses use to defeat host immune defenses and role of ORF45 in viral infection and pathogenesis. In addition, our research may also suggest novel therapeutic target and strategies in treatment of KSHV-associated malignancies.